Wednesday, 19 November 2014

ClinicSpeak: derisking alemtuzumab

Can we make alemtuzumab safer by preventing secondary autoimmunity? #ClinicSpeak #MSBlog #MSResearch

"I am not ignoring alemtuzumab, I only have so many hours in my day to write posts for the blog. However, to reiterate I was at a meeting last week and got into a debate with colleagues about treating MS. I made the point that only the highly-effective treatments are capable of switching off inflammation, allowing spontaneous recovery and preventing end-organ damage; that is in the majority of MSers treated early. Knowing this who would not want to be on a highly-effective treatment? Their response was all about the risks of this strategy, and no necessarily the benefits. If you could make alemtuzumab and natalizumab safe then yes, most neurologists would prescribe them first-line, assuming that they were affordable and available to all. I say this because pharmaceutical pricing is about the risk:benefit ratio and not the manufacturing costs. I note some of you have already commented on the price of Lemtrada compared to Campath, despite them being the same drug.


If the infusion reactions, infections and secondary autoimmunity problems went away who would choose anything but alemtuzumab to treat MS?

Can we reduce the infusion reactions of alemtuzumab? Yes, I think we can.

The oncologists have been using alemtuzumab longer than we have in neurology and they have learnt to pre-treat with steroids starting the night before the first infusion to reduce the infusion reactions. We have also observed that infusion reactions tended to be quite bad on day 4 & 5 during the first course; days that weren't covered by steroid infusions in the trial protocol. We have now included pre-dosing (night before) and give intravenous steroids before all infusions; it works infusion reactions don't seem to be a problem. Another innovation that will come is the subcutaneous route of administration. The oncologists have shown that you get the same therapeutic effect of alemtuzumab, with reduced infusion reaction, when the drug is given by subcutaneous injection, because the cell lysis occurs more slowly. You may be interested that there have already been some exploratory trials of the subcutaneous route in MS (see Perumal et al. abstract below).  

What about preventing or reducing the incidence of secondary autoimmunity?

The immune system has many mechanisms in place to prevent autoimmunity. When you learn how the immune system works it is really quite surprising that autoimmunity is so uncommon. What the immunologists tell us is that there must be a series of underlying biological processes that are causing secondary autoimmunity and if we can work out what these are we can intervene and prevent this complication. This is what the Reverend Dr Coles is currently trying to do in Cambridge. He thinks that because the immune system reboots itself from peripheral memory cells it is more likely to result in an aberrant autoimmune responses. He is currently doing a trial to encourage rebooting of the immune system using more naïve cells from the thymus. He is therefore treating MSers after alemtuzumab with a hormone called, Palifermin, that stimulates the thymus to produce more naïve T-cells. The study is called the Cam-Thy study and is still recruiting subjects.

Interestingly, when you compare cladribine, another immune system rebooter, with alemtuzumab you can’t help but notice that the B-cell reconstitution profiles are very different. With alemtuzumab they comeback very quickly and overshoot their baseline values. We have hypothesised that if you changed the profile of the B cell reconstitution with a small dose of the B cell depleting antibody rituximab you may be able to prevent this secondary autoimmunity. We are really talking about a very small dose of rituximab, i.e. 10-20mg, just enough to allow to delay B cell reconstitution by 4-6 months. I proposed this concept to Genzyme several years ago, but without data to support this they were not keen to support an exploratory study. The problem is that we don’t have any animal models of reconstitution autoimmunity to test these hypotheses so the only thing left for us is to test them in MSers. I personally think Genzyme will regret not supporting the rituximab proposal; the secondary add-on studies would have taught us a lot about secondary autoimmunity.


Another option is to use alemtuzumab in combination with an immunomodulatory agent to try and prevent autoimmunity emerging. For example, to start a drug such as azathioprine or teriflunomide 4-8 weeks after completing the first course of infusions. The idea would be to prevent T-cell priming, proliferation and later B-cell stimulation. My concerns with this strategy is safety; rebooting the immune system in the presence of drugs that are designed to limit T cell proliferation may result in significant immunosuppression. In addition, using high costs drugs such as teriflunomide may make this strategy too expensive. Several different investigators have proposed to Genzyme to bungle alemtuzumab with teriflunomide as a novel way to sequence these two drugs and at the same time de-risking alemtuzumab. The last I heard was that Genzyme-Sanofi was not interested in this strategy. Why? I think they have their own plans to test a treatment strategy to reduce the secondary autoimmunity. If they have their own plans they should start their trials sooner than later. Assuming ocrelizumab (anti-CD20) makes it through the development pipeline as a high-efficacy DMT it is likely to be much safer than alemtuzumab and natalizumab and hence is likely to corner the market. If this occurs then alemtuzumab is likely to remain a very niche drug used is small numbers of MSers. I have actually heard someone say that alemtuzumab has a sell by date on it; the date being the day ocrelizumab gets its license. I don't necessarily agree with this comment, simply because alemtuzumab has better long-term remission data than ocrelizumab and it may offer an MS cure in a proportion of MSers. I think for some MSers the latter may be what is important.

Another way of de-risking alemtuzumab is to open up the secondary autoimmunity problem to the wider immunology community as a human model to study organ specific autoimmune diseases in. MSers treated with alemtuzumab can then be used to test organ-specific immune tolerance strategies. 

Can we re-educate the reconstituting immune system with a cocktail of proteins from the thyroid gland to teach the newly emerging T-cells to ignore the thyroid gland? 

The problem with antigen-specific immune tolerance is that you will need to have a different cocktail of proteins for each autoimmune disease. Starting with thyroid autoimmunity would make the most sense; it is the commonest autoimmune disease post-alemtuzumab and we know quite a lot about the putative autoantigens involved. We are in the process of preparing a grant application to tackle thyroid autoimmunity; however, we need to start in animal model first before we can move into MS.

Getting rid of the secondary autoimmunity problem will not de-risk alemtuzumab completely. Why? The infectious complications when the immune system is depleted for a few weeks, to months, after each course will remain. In addition, there is still the unanswered question about a delayed secondary malignancy risk. The latter will take decades to be answered in the so called post-marketing surveillance programme. Another concern with immune system rebooters is premature ageing of the immune system, or immunosenescence, this is when the immune system loses its memory to many common infections. Why this occurs is debatable, but is associated with a shrinking of the so called immune repertoire. The repertoire becomes dominated by T cell responses to latent viruses for example CMV (cytomegalovirus) and EBV (Epstein Barr virus)."
 


Perumal et al. Subcutaneous administration of alemtuzumab in patients with highly active multiple sclerosis. Mult Scler. 2012 Aug;18(8):1197-9.

Alemtuzumab is an anti-CD52 monoclonal antibody with remarkable efficacy in relapsing multiple sclerosis (MS). In clinical trials and off-label use in MS, alemtuzumab has been administered intravenously (IV). Alemtuzumab is approved for chronic lymphoid leukemia as IV. Oncology guidelines recommend alemtuzumab subcutaneous (SC) over IV. There is no report of alemtuzumab SC in MS. We report two patients with highly active relapsing MS who were treated with SC alemtuzumab, had significant improvement and tolerated SC alemtuzumab well without the typical infusion-associated adverse events. SC alemtuzumab in MS warrants further studies as this may enhance patient convenience and minimize infusion-associated adverse events.

CoI: multiple

34 comments:

  1. Dr.G why does Alum seem to cause more secondary Autoimmunity then BMT ?

    ReplyDelete
    Replies
    1. Re: "Dr.G why does Alum seem to cause more secondary Autoimmunity then BMT ?"

      I am not sure it does; too few MSers have had BMT and reported to confident it does. But if it does it may relate to the different type of immune reconstitution you get with BMT. Another reason why we need to try and change the kinetics of immune reconstitution to see if we alter the incidence of secondary autoimmunity.

      Delete
    2. Thanks Dr :) .. Possibly because of the stem cell infusion and deeper ablation leading to a more naive subset of lymphocytes opposed to prephepial expansion ? Alum followed by stem cell infusion should be tried .. A bonus : it will speed up immune reconstruction and reduce risk of infections !

      Delete
  2. As far as I know , it's not clear yet if anti-cd20 is an induction or maintenance therapy ..

    ReplyDelete
    Replies
    1. Re: " it's not clear yet if anti-cd20 is an induction or maintenance therapy."

      I agree, we need to know a lot more about durability of the response and the retreatment frequency. But the issue is not really about induction vs. non-induction. If you want a very high efficacy DMT and you have to chose between natalizumab vs. alemtuzumab vs ocrelizumab; what will you choose?

      Delete
    2. As an MSER with minor symptoms so far (it's been a year) ,I am willing to take resonable risks to stay where I am...

      I want an induction therapy .. Okay now I have work group insurance but I constanly worry what I will do if I loose my job ! (I'm an expat in Dubai , so no public healthcare coverage)

      So it's cd20 vs alum for me depending on further cd20 trial results and if alum can be de-risked as you are sudjesting.

      I'll be posting under this name as I've decided to exit the anon crowd :)

      Cheers and thanks for this great blog !

      Delete
  3. What do we know / expect about safety issues with ocrelizumab / anti-CD20, especially when used long-term?
    Will premature ageing of the immune system be a concern there too?

    ReplyDelete
    Replies
    1. Re: "What do we know / expect about safety issues with ocrelizumab / anti-CD20, especially when used long-term?"

      We know quite a lot; rituximab has been around a long time in the RA space and it seems okay.

      Re: "Will premature ageing of the immune system be a concern there too?"

      Probably not; my understanding is that immune senescence applies to the T-cell compartment. If you antibody levels drop too low you can always replace them with hyperimmune globulin; you can't do the same when it comes to T cells.

      Delete
  4. Are you suggesting that cladribine would be a better option that alemtuzumab?

    ReplyDelete
    Replies
    1. Re: "Are you suggesting that cladribine would be a better option that alemtuzumab?"

      Absolutely; what we really need is a head-2-head study of cladribine vs. alemtuzumab. I would not be surprised if they level peg in terms of long-term efficacy when used early in MS, but cladribine would win hands down when it comes to safety. The problem is we don't have a licensed form of cladribine for MS.

      Delete
    2. Not yet but hopefully this is going to change.

      Delete
    3. Well if the white knights are successful, then yes.

      Delete
    4. It'd be cheap as chips too, though I suspect a big pharma hit squad would be dispatched pronto were they to be successful. ;-)

      Delete
    5. Finally! A CLUE ABOUT THE WHITE KNIGHT POSTS

      Delete
  5. Prof G - what is key to MS'ers is reliable data, you have mentioned that you believe Alemtuzumab could be a cure, but surely you need data to back this up? If Alemtuzumab gives me stability during RRMS but then when I reach the age/time then SPMS hits me, then it is not a cure, it is a drug that puts the disease into remission. (same with Natalizamab) Do you agree or do you genuinely believe that Alemtuzumab is a cure (even those Prof Coles states it is not)

    I'm also curious - what data backs up the statement that Alemtuzumab and BMT have the same efficacy?.

    ReplyDelete
    Replies
    1. I have never said a cure either; I always state a "potential cure". For example in this post I state "may offer an MS cure".

      We simply have not followed up alemtuzumab-treated MSers for long enough. It is an experiment that is currently running.

      http://multiple-sclerosis-research.blogspot.com/2013/02/neda-defining-cure.html

      http://multiple-sclerosis-research.blogspot.com/2010/03/defining-what-cure-means-in-multiple.html

      Regarding BMT; there are lots of publications on this and we have posted on this in the past. The BMT data looks very good; may be better than alemtuzumab.

      http://multiple-sclerosis-research.blogspot.com/2011/12/bone-marrow-transplantation-bmt.html

      Delete
    2. At a personal level if alemtuzumab or BMT did not offer a potential cure, or put another way a long-term remission, the risks would not be worth taking.

      Delete
    3. Do you think the same of nataluzamab? Also, your FACULTI YouTube video says you think some drugs offer a cure I think - then go on to talk about Alemtuzumab.

      What about both? Do BMT and then folllow up with alemtuzamab, in some of the intl centres offering BMT you get Alem or Rituxan as part of treatment.

      Delete
    4. The only way to work out what is best is a head to head. One neuro tried to do this but did not get support to do this yet

      Delete
  6. Prof G,
    Should we discontinue vitD supplementation after this?
    Increased vitamin D is associated with decline of naïve, but accumulation of effector, CD8 T cells during early aging
    http://file.scirp.org/Html/3-2420030_31315.htm
    At least post alemtuzumab?

    ReplyDelete
    Replies
    1. ProfG can answer but I would not stop yet until it is proven to be bad...everything is in balances and inducing old age in CD8..what does this mean..Vitamin D gives you proven bone health

      Delete
  7. Ona previous post you said:

    "Just imagine if the PML problem went away, and natalizumab was shown to be safe in pregnancy, who would choose anything but natalizumab to treat MS?"

    On this post you say: "If the infusion reactions, infections and secondary autoimmunity problems went away who would choose anything but alemtuzumab to treat MS?"

    In an ideal scenario where all risk factors were taken out of the equation, which treatment should one choose?

    ReplyDelete
    Replies
    1. Re: "In an ideal scenario where all risk factors were taken out of the equation, which treatment should one choose? "

      A very good question; I suggest you read the following post:

      http://multiple-sclerosis-research.blogspot.com/2014/08/clinicspeak-natalizumab-or-alemtuzumab.html

      There is no easy answer; your choice depends on your treatment philosophy.

      Delete
    2. This is Anon:10:25.

      Assuming one is agnostic to treatment philosophy but would want to achieve the best outcome, which treatment would you advise him to pursue please?

      Delete
    3. It's a choice between one-time (or rather two-time) treatment vs monthly infusions.

      If all risk factors were taken out of the equation, alemtuzumab would not even need the monthly blood tests

      Then the choice would have to be alemtuzumab

      Delete
    4. But then hassle value (i.e. monthly v.s. one-off) is a minor cost in the grand scheme of things and would fit under treatment philospohy in my view.

      My question relates solely to efficacy and benefit

      Delete
  8. Prof G,

    the term 'immunosenescence' is not one I've heard before with regards to alemtuzumab. It sounds more worrisome and uncertain than the risks of autoimmunity, particularly for the longer term. Does this mean there is ageing of a subset of cells in the immune system, is it an imbalance of cell types, or is there some affect on the immune system as a whole? Would this particular factor have any relationship to risks of infections and cancer in the longer term after the drug (e.g. 20 years down the line)?

    many thanks as always for an excellent, honest blog.

    ReplyDelete
    Replies
    1. there is senescence in every thing and in the immune response too. This can clearly be shown in those dodgy experiments when they sew a young mouse to an old mouse. The old mouse cells are less efficient at clearing up debris which is needed before repair.

      Delete
  9. Now I'm thinking maybe the smart thing to do would be to get on natalizumab for two or three years--especially if I test negative for JCV. And let the industry derisk alemtuzumab or get ocrelizumab or clabridine to market. The landscape is dramatically different today even compared to when I was diagnosed 3 years ago--when neuros wouldn't dream of giving me Tysabri until I was a lot sicker. Now many are prescribing it first line. Attitudes change; drugs change; etc. Three years from now, I expect the landscape will be dramatically different again. Effective therapies might be safer yet. Natalizumab won't cure anybody, true. But won't it hold us steady while we're waiting for the cure?

    I know you don't address individual cases, but I just thought I'd throw that out there and see if something percolates in your writing later as you talk about treatment strategies.

    ReplyDelete
  10. By the way, would regular B-cell depletion by anti-cd20's eventually result in reduced bone morrow output? Isn't division capacity of progenitor cells limited?

    ReplyDelete
  11. I had a conversation regarding this drug with my neuro yesterday. Its not been used in the trust yet, will be considered for a 2nd line therapy for "very bad ms" due to the high risks.

    ReplyDelete
    Replies
    1. What about the high risks of not effectively treating MS at an early stage? MSers need to educate themselves about all the alternatives. Some neuros would rather stay with the 'safe' mildly effective DMTs and if you end up in a wheelchair later along the line, well, that's the natural course of the disease.

      Delete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.